5-HT6 receptor is one of the potential therapeutic target for the development of cognitive enhancers: for the treatment of Alzheimer's disease (AD) and schizophrenia. 5-HT6 receptor is localized exclusively in central nervous system, in areas important for learning and memory. In recent years several studies (Brain Research, 1997, 746, 207-219; Journal of Neuroscience, 1998, 18(15), 5901-5907; International Review of Neurobiology Volume 96, 2011, 27-47 & Annual Reviews in Pharmacology and Toxicology, 2000, 40, 319-334a) have reported that 5-HT6 receptor antagonists show beneficial effect on cognition in animal models.
Suven Life Sciences Ltd is developing 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate, which is a selective 5-HT6 receptor antagonists intended for the symptomatic treatment of AD and other disorders of memory and cognition like attention deficient hyperactivity, parkinson's and schizophrenia. 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole, and its pharmaceutically acceptable salts were disclosed by Ramakrishna et al. in WO 2004/048330.
1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate has already completed Phase I clinical trials. Based on phase I clinical trials results, we confirmed 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(1-piperazinyl)methyl]-1H-indole of formula (I) as an active metabolite of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate in human volunteers.
The development and understanding of the metabolism of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate is desirable for progression of science and necessary step in the commercialization of this compound. Therefore, there is a need to understand regarding metabolism and metabolites of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate.
In order to improve pharmaceutical properties and efficacy of active metabolite, we performed salt selection program for 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(1-piperazinyl)methyl]-1H-indole. Based on the results obtained, dimesylate dihydrate salt of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(1-piperazinyl)methyl]-1H-indole of formula (II) is selected for further development along with the compound of formula (I).